tbuckley/cabot-search huggingface dataset:
Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress
Authors: Ken Uekawa, Yorito Hattori, Sung Ji Ahn, James Seo, Nicole Casey, Antoine Anfray, Ping Zhou, Wenjie Luo, Josef Anrather, Laibaik Park, Costantino Iadecola
Journal: Molecular Neurodegeneration (2023)

Abstract Background Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. Methods Tg2576 mice and WT littermates were transplanted with CD36 −/− or CD36 +/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36 −/− BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. Results The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36 −/− → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ 1-40 , but not Aβ 1-42 , was reduced in CD36 −/− → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36 −/− → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36 −/− mice were able to more efficiently clear exogenous Aβ 1-40 injected into the neocortex or the striatum. Conclusions CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ 1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage. Graphical Abstract
Boostability after single-visit pre-exposure prophylaxis with rabies vaccine: a randomised controlled non-inferiority trial
Authors: Lisanne A Overduin, Jan Pieter R Koopman, Corine Prins, Petra H Verbeek-Menken, Cornelis A De Pijper, Phaedra L Eblé, Fiona Heerink, Perry J J van Genderen, Martin P Grobusch, Leo G Visser
Journal: The Lancet Infectious Diseases (2023)
Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome
Authors: Lu-Ping Yang, Teng-Jia Jiang, Ming-Ming He, Yi-Hong Ling, Zi-Xian Wang, Hao-Xiang Wu, Zhen Zhang, Rui-Hua Xu, Feng Wang, Shu-Qiang Yuan, Qi Zhao
Journal: Cell Reports Medicine (2023)

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.
End binding-3 inhibitor activates regenerative program in age-related macular degeneration
Authors: Quinn Lee, Wan Ching Chan, Xinyan Qu, Ying Sun, Hazem Abdelkarim, Jonathan Le, Uzma Saqib, Mitchell Y. Sun, Kevin Kruse, Avik Banerjee, Ben Hitchinson, Melissa Geyer, Fei Huang, Victor Guaiquil, Amelia A. Mutso, Martin Sanders, Mark I. Rosenblatt, Mark Maienschein-Cline, Matthew S. Lawrence, Vadim Gaponenko, Asrar B. Malik, Yulia A. Komarova
Journal: Cell Reports Medicine (2023)

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.
Dasatinib anhydrate containing oral formulation improves variability and bioavailability in humans
Authors: Jiří Hofmann, Aleš Bartůněk, Tomáš Hauser, Gregor Sedmak, Josef Beránek, Pavel Ryšánek, Martin Šíma, Ondřej Slanař
Journal: Leukemia (2023)

Abstract Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both C max and AUC of dasatinib were within standard 80.00–125.00% range, while the intra- and inter-subject variability for AUC 0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively. In a drug–drug interaction study, omeprazole 40 mg reduced the mean AUC 0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as &gt;21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC. The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
Correction: Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
Authors: Mike Aoun, Ana Coelho, Alexander Krämer, Amit Saxena, Pierre Sabatier, Christian Michel Beusch, Erik Lönnblom, Manman Geng, Nhu-Nguyen Do, Zhongwei Xu, Jingdian Zhang, Yibo He, Laura Romero Castillo, Hassan Abolhassani, Bingze Xu, Johan Viljanen, Joanna Rorbach, Gonzalo Fernandez Lahore, Inger Gjertsson, Alf Kastbom, Christopher Sjöwall, Jan Kihlberg, Roman A. Zubarev, Harald Burkhardt, Rikard Holmdahl
Journal: The Journal of Experimental Medicine (2023)

In the originally published article, the figure images for Figs. 4 and S4 were accidentally swapped with Figs. 5 and S5, respectively; the legends remain unchanged.The corrected figures and their legends are shown here.In addition, figure citations and a typographical error were corrected in the Results and Materials and methods.Changes are indicated with underlined text as follows: ResultsAntigen-presenting C1-B induce COL2-specific Treg proliferation in a contact-dependent manner Despite the ability of C1-B in secreting IL10 (Fig. S3 C), we failed to detect a prominent proliferation of Tregs in the contactless set-up. C1-B hold an antigen presentation signature and upregulate CCR7 and CD72 upon activationWhile we showed that autoreactive C1-B exist in mice and men and on the transcriptional level mouse and human gene profiles are overall conserved, we chose to define the more relevant C1-B from HD by transcriptomics to later validate the hits in the mouse.To better delineate the C1-B population, we immunophenotyped LN-derived cells from BQ mice 30 d after COL2 immunization (Fig. 5 K). Materials and methods Serum and cartilage samplesSerum samples, used in Fig. S1 F, from three different cohorts were employed.
Recruitment of naive CD4+ T cells by the recombinant zoster vaccine correlates with persistent immunity
Authors: Kerry J. Laing, Emily S. Ford, Michael J. Johnson, Myron J. Levin, David M. Koelle, Adriana Weinberg
Journal: Journal of Clinical Investigation (2023)

Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the two vaccines, we used T cell receptor beta sequencing and peptide-MHC class II tetramer staining to analyze gE-specific CD4+ T cell clonotypes in RZV and ZVL recipients. Compared to ZVL, RZV expanded more gE-specific CD4+ clonotypes with greater breadth and higher frequency of public clonotypes. RZV recruited a higher proportion of clonotypes from the naïve than from memory cells, while ZVL recruited equally from memory and naïve compartments. Compared to memory-, naïve-derived clonotypes were more likely to last ≥ 5 years post-immunization. Moreover, the frequency of tetramer+ persistent clones correlated with the frequency of tetramer+ naïve CD4+ T cells pre-vaccination. We conclude that the ability of RZV to recruit naive CD4+ T cells into the response may contribute to the durability of its effect. The abundance, breadth, and the frequency of public clonotypes may further add to its protective effect.
Loss and damage responses to climate change
Authors: Rita Issa, Adelle Thomas, Noora Firaq, Arthur Wyns
Journal: BMJ (2023)

This year has seen wildfires, flash flooding, and the warmest month on record, 1 a likely "new normal" as the consequences of climate change-primarily driven by burning fossil fuels for energy-unfold.Both extreme weather events-such as heatwaves and cyclones, and slowly unfolding crises-such as desertification and food insecurity, pose well described threats to our health and wellbeing. 2As such, this year's UN annual climate conference (COP28, running from 30 November to 12 December 2023), will have an unprecedented focus on health in recognition that ill health is a key downstream consequence of inadequate climate policy, and that putting health at the centre of decision making can help drive decisive climate action.
Great Britain risks losing one in six wildlife species
Authors: Alison Shepherd
Journal: BMJ (2023)

The UK is now one of the most nature depleted countries on Earth.That is the conclusion of a major report on the state of the country's ecosystem.Like most other countries, the UK has experienced a significant loss of biodiversity in the past 50 years, but with one in six species in Great Britain deemed at risk of extinction (assessed by the International Union for the Conservation of Nature as critically endangered, endangered, or vulnerable) it is particularly hard hit, says the State of Nature 2023 report (https://stateofnature.org.uk).The distribution of the brown hare (pictured) in Great Britain fell by 15% between 1970 and 2015.Most of the important habitats for nature are in poor condition, but, more optimistically, the report says that it is not too late and that "restoration projects can and do have clear benefits for nature and people, as well as climate change mitigation and adaptation."State of Nature, the most comprehensive nature report covering the UK, is the product of work by more than 60 research and conservation organisations.It shows that the intensive way in which we manage our land for farming and the continuing effects of the climate emergency are the two biggest drivers of nature loss.At sea, unsustainable fishing and climate are the major contributing factors.
<i>HLA-DPA1*02:01~B1*01:01</i>is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells
Authors: Britta F Zecher, David Ellinghaus, Sebastian Schloer, Annika Niehrs, Benedetta Padoan, Martin E Baumdick, Yuko Yuki, Maureen P Martin, Dawid Glow, Jennifer Schröder-Schwarz, Jennifer Niersch, Sébastien Brias, Luisa M Müller, Robin Habermann, Paul Kretschmer, Tristan Früh, Janis Dänekas, Malte H Wehmeyer, Tobias Poch, Marcial Sebode, Eva Ellinghaus, Frauke Degenhardt, Christian Körner, Angelique Hoelzemer, Boris Fehse, Karl J Oldhafer, Udo Schumacher, Guido Sauter, Mary Carrington, Andre Franke, Madeleine J Bunders, Christoph Schramm, Marcus Altfeld
Journal: Gut (2023)

Objective Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. Design Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. Results NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10 −50 ). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.
Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients
Authors: Victoria Panagiota, Johanna Franziska Kerschbaum, Olaf Penack, Catarina M. Stein, Christopher M. Arends, Christian Koenecke, Paulina M. Strzelecka, Arnold Kloos, Laura Wiegand, Alina Lasch, Robert Altwasser, Adriane Halik, Razif Gabdoulline, Julia Thomson, Konstantin Weibl, Georg-Nikolaus Franke, Carolina Berger, Justin Hasenkamp, Francis Ayuk, Il-Kang Na, Gernot Beutel, Ulrich Keller, Lars Bullinger, Gerald Georg Wulf, Nicolaus Kröger, Vladan Vucinic, Michael Heuser, Frederik Damm
Journal: HemaSphere (2023)

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.
USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis
Authors: Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou
Journal: Journal of Clinical Investigation (2023)

The functional integrity of Treg cells is interwoven with cellular metabolism; however, the mechanisms governing Treg cell metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited RNA m6A reader YTHDF1-mediated c-Myc translation to maintain Treg cell metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg cell signature in colorectal cancer and gastric cancer patient samples. USP47 ablation compromised Treg cell homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Treg cells triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg cell homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting USP47.
Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis
Authors: Danielle N. Alfano, Mark J. Miller, Juliane Bubeck Wardenburg
Journal: Journal of Clinical Investigation (2023)

The endothelium plays a critical role in the host response to infection, and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate herein that endothelial ADAM10 is essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to a-toxin (Hla)-mediated microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in pathogenesis. Mice harboring an endothelial-specific knockout of ADAM10 are protected against lethal Pseudomonas aeruginosa and Streptococcus pneumoniae sepsis, yet remain fully susceptible to Group B Streptococci and Candida albicans sepsis. These studies illustrate a previously unknown role for ADAM10 in sepsis-associated endothelial injury, and suggest that understanding pathogen-specific divergent host pathways in sepsis may enable more precise targeting of disease.
A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G&gt;T
Authors: Kentaro Ito, Go Tajima, Chikako Kamisato, Miyuki Tsumura, Mitsuhiro Iwamoto, Yukiko Sekiguchi, Yukinobu Numata, Kyoko Watanabe, Yoshiyuki Yabe, Satomi Kanki, Yusuke Fujieda, Koichi Goto, Yoshitaka Sogawa, Masataka Oitate, Hiroyuki Nagase, Shinnosuke Tsuji, Tomohiro Nishizawa, Masayo Kakuta, Takeshi Masuda, Yoshiyuki Onishi, Makoto Koizumi, Hidefumi Nakamura, Satoshi Okada, Masafumi Matsuo, Kiyosumi Takaishi
Journal: Journal of Clinical Investigation (2023)

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-alpha (G6Pase-α, encoded by G6PC), primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves the life expectancy, patients still suffer from intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a, but potentially require complicated glycemic management throughout life. Here, we present a oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. A generated mouse strain with homozygous knock-in of this variant well reflected the pathophysiology of GSD1a patients. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b exhibited long-lasting efficacy for more than 12 weeks in the mice with a single dose and favorable pharmacokinetics and tolerability in mice and monkeys. Taking these findings together, this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.
Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer
Authors: Miguel J. Franquiz, Sarah Waliany, Audrey Yingwei Xu, Anna Hnatiuk, Sean M. Wu, Paul Cheng, Heather A. Wakelee, Joel Neal, Ronald Witteles, Han Zhu
Journal: JACC CardioOncology (2023)
Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards
Authors: Holm H. Uhlig, Claire Booth, Judy Cho, Marla Dubinsky, Anne M. Griffiths, Bodo Grimbacher, Sophie Hambleton, Ying Huang, Kelsey Jones, Jochen Kammermeier, Hirokazu Kanegane, Sibylle Koletzko, Daniel Kotlarz, Christoph Klein, Michael J. Lenardo, Bernice Lo, Dermot P. B. McGovern, Ahmet Özen, Lissy de Ridder, Frank Ruemmele, Dror S. Shouval, Scott B. Snapper, Simon P. Travis, Dan Turner, David C. Wilson, Aleixo M. Muise
Journal: Nature Reviews Gastroenterology & Hepatology (2023)